NM_004136.4:c.2472+12A>C

Variant names:

• chr15-78494068-A-C
• rs4887060
• NM_004136.4:c.2472+12A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004136.4(IREB2):​c.2472+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,748 control chromosomes in the GnomAD database, including 798,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72065 hom., cov: 32)
  • Exomes 𝑓: 1.0 (726912 hom.)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00800
• Publications: 9 publications found

Genes affected

IREB2 (HGNC:6115): (iron responsive element binding protein 2) The protein encoded by this gene is an RNA-binding protein that acts to regulate iron levels in the cells by regulating the translation and stability of mRNAs that affect iron homeostasis under conditions when iron is depleted. When iron levels are low, this protein binds to iron-responsive elements (IRES), stem-loop structures located either in the 5' or 3' UTRs. Binding to the 5' UTR represses translation, while binding to the 3' UTR inhibits mRNA degradation. When iron is found in the cell, this protein is degraded in a F-box and leucine rich repeat protein 5-dependent manner. Variants in this gene have been associated with lung cancer and chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

IREB2 Gene-Disease associations (from GenCC):

• neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-78494068-A-C is Benign according to our data. Variant chr15-78494068-A-C is described in ClinVar as Benign. ClinVar VariationId is 1300042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.2472+12A>C		intron_variant	Intron 19 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.2301+12A>C		intron_variant	Intron 19 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.2301+12A>C		intron_variant	Intron 19 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.1722+12A>C		intron_variant	Intron 18 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2472+12A>C		intron_variant	Intron 19 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*1739+12A>C		intron_variant	Intron 18 of 20	1		ENSP00000454063.1
IREB2	ENST00000559091.1	c.-143A>C		upstream_gene_variant		3		ENSP00000453863.1

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147871 AN: 152156 Hom.: 72013 Cov.: 32

Gnomad AFR AF: 0.901

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.982

GnomAD2 exomes AF: 0.993 AC: 248393 AN: 250114 AF XY: 0.995

Gnomad AFR exome AF: 0.901

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.997 AC: 1457464 AN: 1461474 Hom.: 726912 Cov.: 46 AF XY: 0.998 AC XY: 725311 AN XY: 727036

African (AFR) AF: 0.903 AC: 30182 AN: 33440

American (AMR) AF: 0.995 AC: 44427 AN: 44628

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26105 AN: 26106

East Asian (EAS) AF: 1.00 AC: 39678 AN: 39678

South Asian (SAS) AF: 1.00 AC: 86204 AN: 86214

European-Finnish (FIN) AF: 1.00 AC: 53414 AN: 53414

Middle Eastern (MID) AF: 0.995 AC: 5738 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111721 AN: 1111852

Other (OTH) AF: 0.994 AC: 59995 AN: 60374

GnomAD4 genome AF: 0.972 AC: 147983 AN: 152274 Hom.: 72065 Cov.: 32 AF XY: 0.974 AC XY: 72488 AN XY: 74444

African (AFR) AF: 0.901 AC: 37393 AN: 41510

American (AMR) AF: 0.992 AC: 15182 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68024 AN: 68038

Other (OTH) AF: 0.982 AC: 2078 AN: 2116

Alfa AF: 0.992 Hom.: 93985

Bravo AF: 0.968

Asia WGS AF: 0.994 AC: 3455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.88
DANN	Benign	0.57
PhyloP100		-0.0080
PromoterAI		-0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4887060; hg19: chr15-78786410;